This following blog is near and dear to me. My father was diagnosed last May/June with a highly aggressive brain tumor. He has done a few different treatments including two different surgeries to remove the cancer grow and regrowth. the information in this blog is to help others that may have no other options. Please note this is not a cure it is just to help slow down or stop the growth. I have included the steps of how the trial phase is run and the drug information as best to my ability. This medication is still in its Trial phases and my father has has good results. Some trials may also be done with slightly different med combinations. Please feel free to comment or ask questions.
May is National Brain Tumor Awareness Month
Brain tumors do not discriminate. Primary brain tumors – those that begin in the brain and tend to stay in the brain – occur in people of all ages, but they are statistically more frequent in children and older adults. Metastatic brain tumors – those that begin as a cancer elsewhere in the body and spread to the brain – are more common in adults than in children. Metastatic brain tumors are the most common brain tumor, with an annual incidence more than four times greater than that of primary brain tumors. Cancers that most commonly metastasize to the brain are lung and breast. In the United States, an estimated 61,414 new cases of primary brain tumors are expected to be diagnosed in 2009. Of this total number, an estimated 37% will be malignant and 63% will be benign.
Avastin and Tarceva (Erlotinib) Trial - Malignant Gliomas:
A PHASE II STUDY OF AVASTIN® (Bevacizumab) AND TARCEVA® (Erlotinib) AFTER RADIATION THERAPY AND TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME WITHOUT MGMT PROMOTER METHYLATION (IRB #19965)
Malignant gliomas are the most common brain
tumor in adults with about 15,000-17,000 new cases each year in the
United States. The typical median survival is approximately 12 months
for patients with newly diagnosed glioblastoma (GBM) and 24-36 months
for patients with anaplastic astrocytoma. Current standard therapy can
treat this type of cancer but in most cases the tumor returns. Standard
therapy is radiation therapy combined with temozolomide. This treatment
works best for patients who have a certain gene called MGMT turned "off"
(methylated).
This study involves the
combination of radiation therapy and temzolomide as part of normal
standard therapy. The patient's tumor will be tested for MGMT status. If
the MGMT gene is not turned "off", subjects will be treated with
Avastin (which inhibits blood vessel growth) and Erlotinib
(Tarceva--which inhibits a receptor called EGFR). If the MGMT gene is
turned "off", subjects will receive standard of care therapy.
Avastin
has been approved by the Food and Drug Administration (FDA) for colon
cancer, breast cancer, and lung cancer and has reported activity in
brain tumors. Erlotinib has been approved by the FDA for lung cancer and
pancreatic cancer. Avastin and Erlotinib have not yet been approved by
the FDA for glioblastoma and are considered investigational. The purpose
of this study is too evaluated whether this combination is better than
maintenance with temozolomide after radiation therapy.
Once a patient signs the main consent form, tissue used to confirm diagnosis or surgery will be sent for MGMT analysis to determine whether or not the gene is "on" or "off". Please note, patients who do not have tissue available for central review will not be eligible to participate in this study. While this analysis is taking place, subjects will begin standard treatment (with radiation and temozolomide) for 7 weeks. Once the 7 week standard therapy is complete, subjects will have an MRI done. If the results of the MRI show that the tumor has remained stable or has decreased in size, the subject may continue on trial. If the tumor has grown, subjects will not be allowed to participate in this trial. It is at this point that the analysis of the MGMT gene in the tumor will be shared with the subject. If the MGMT gene is not active in the subject's tumor, the subject will be removed from the study and will continue to receive standard of care treatment for their condition. If the MGMT gene is active in the subject's tumor, the subject will be given Avastin every 2 weeks as an intravenous infusion (over 30-90 minutes) and will take Erlotinib orally daily. Patients will remain on the study for up to one year as long as the study treatment is working. The following procedures will also be done during subject's participation in this trial:
Once a patient signs the main consent form, tissue used to confirm diagnosis or surgery will be sent for MGMT analysis to determine whether or not the gene is "on" or "off". Please note, patients who do not have tissue available for central review will not be eligible to participate in this study. While this analysis is taking place, subjects will begin standard treatment (with radiation and temozolomide) for 7 weeks. Once the 7 week standard therapy is complete, subjects will have an MRI done. If the results of the MRI show that the tumor has remained stable or has decreased in size, the subject may continue on trial. If the tumor has grown, subjects will not be allowed to participate in this trial. It is at this point that the analysis of the MGMT gene in the tumor will be shared with the subject. If the MGMT gene is not active in the subject's tumor, the subject will be removed from the study and will continue to receive standard of care treatment for their condition. If the MGMT gene is active in the subject's tumor, the subject will be given Avastin every 2 weeks as an intravenous infusion (over 30-90 minutes) and will take Erlotinib orally daily. Patients will remain on the study for up to one year as long as the study treatment is working. The following procedures will also be done during subject's participation in this trial:
- A pregnancy test (if female of childbearing potential) will be done before the first cycle of treatment. A blood sample (about 1 teaspoon of 5 mL) will be taken
- Electrocardiogram (EKG—a test that measures the electrical activity of the heart) may be done before first cycle if deemed medically necessary by the study doctor.
- Neurological exam (including blood pressure and heart rate) will be done on Day 1 of each cycle.
- Urine test will be done Day 1 of each cycle.
- Blood test (approximately 2-3 teaspoons or 10-15 mL) will be done Day 1 of each cycle.
- Subjects will be asked to record any side effects they experience
- MRI with contrast (including optional MR Perfusion) will be performed every 2 cycles.
Approximately
10 subjects will take part in this research study at Cedars-Sinai. A
total of 50 subjects will participate in the study nationwide. Please
note that the subject and their insurance company will not be charged
for the study drugs (Avastin and Erlotinib) given in this trial.
However, while the study team will supply the subject with these drugs,
the subject or their insurance company will be responsible to pay for
the administration of Avastin. Depending on the time frame of the
subject's enrollment, there may be one MRI that falls outside of
standard of care procedures. If this is the case, the MRI will be
considered a research related procedure and will not be charged to the
subject or their insurance company. All other procedures are considered
standard of care and will be billed to the subject or their insurance
company.
Patients will be followed-up by
the study doctor and staff every 3 months until death, if possible.
These follow-up visits are considered standard of care. If a patient
chooses to no longer come into the clinic, a member of the study staff
will call the patient to determine survival.
®
as dyspnea, cough and fever occur. Discontinue TARCEVA if ILD is diagnosed. (5.1) • Cases of acute renal failure (including fatalities), and renal insufficiency have been reported.
Interrupt TARCEVA in the event of dehydration. Monitor renal function and electrolytes in patients
at risk of dehydration. (5.2) • Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported.
Monitor periodic liver function testing. Interrupt or discontinue TARCEVA if liver function changes
are severe. (5.3) • Monitor patients with hepatic impairment closely. Interrupt or discontinue TARCEVA if changes in
liver function are severe (5.4) • Gastrointestinal perforations, including fatalities, have been reported. Discontinue TARCEVA. (5.5) • Bullous and exfoliative skin disorders, including fatalities, have been reported. Interrupt or
discontinue TARCEVA (5.6) • Myocardial infarction/ischemia has been reported, including fatalities, in patients with pancreatic
cancer. (5.7) • Cerebrovascular accidents, including a fatality, have been reported in patients with pancreatic
cancer. (5.8) • Microangiopathic Hemolytic Anemia with thrombocytopenia has been reported in patients with
pancreatic cancer. (5.9) • Corneal perforation and ulceration have been reported. Interrupt or discontinue TARCEVA (5.10) • International Normalized Ratio (INR) elevations and bleeding events, some associated with
concomitant warfarin administration have been reported. Monitor patients taking warfarin or other
coumarin-derivative anticoagulants. (5.11) • TARCEVA can cause fetal harm when administered to a pregnant woman. Women should be
advised to avoid pregnancy while on TARCEVA. (5.12)
--------------------------------ADVERSE REACTIONS---------------------------------
• The most common adverse reactions (>20%) in maintenance treatment are rash-like events and diarrhea. (6)
• The most common adverse reactions (>20%) in 2nd line NSCLC are rash, diarrhea, anorexia, fatigue, dyspnea, cough, nausea, infection and vomiting. (6)
• The most common adverse reactions (>20%) in pancreatic cancer are fatigue, rash, nausea, anorexia, diarrhea, abdominal pain, vomiting, weight decrease, infection, edema, pyrexia, constipation, bone pain, dyspnea, stomatitis and myalgia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact OSI Pharmaceuticals Inc. at 1-800-572-1932 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
--------------------------------DRUG INTERACTIONS---------------------------------
• CYP3A4 inhibitors may increase erlotinib plasma concentrations. (7) • CYP3A4 inducers may decrease erlotinib plasma concentrations. (7) • CYP1A2 inducers may decrease erlotinib plasma concentrations. (7) • Erlotinib solubility is pH dependent. Drugs that alter the pH of the upper GI tract may alter the
solubility of erlotinib and hence its absorption. (7) • Cigarette smoking decreases erlotinib plasma concentrations (7)
See 17 for PATIENT COUNSELING INFORMATION. Revised: [4/2010]
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Gender 8.7 Race 8.8 Patients with Hepatic Impairment 8.9 Patients with Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action 12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TARCEVA safely and effectively. See full prescribing information for TARCEVA.
TARCEVA® (erlotinib) tablets, oral Initial U.S. Approval: 2004
----------------------------RECENT MAJOR CHANGES---------------------------
Indications and Usage (1.1) Warnings and Precautions, Gastrointestinal Perforation (5.5) Warnings and Precautions, Bullous Skin Disorders (5.6) Warnings and Precautions, Ocular Disorders (5.10)
04/2010 04/2009 04/2009 04/2009
-------------------------------INDICATIONS AND USAGE-----------------------------
TARCEVA is a kinase inhibitor indicated for:
•
•
•
Maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. (1.1) Treatment of locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. (1.1) First-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer, in combination with gemcitabine. (1.2)
--------------------------DOSAGE AND ADMINISTRATION---------------------------
• The dose for NSCLC is 150 mg/day. (2.1) • The dose for pancreatic cancer is 100 mg/day. (2.2) • All doses of TARCEVA should be taken on an empty stomach at least one hour before or two hours
after food. (2.1, 2.2)
• Reduce in 50 mg decrements, when necessary. (2.3)
------------------------DOSAGE FORMS AND STRENGTHS-------------------------
• Tablets: 25 mg, 100 mg and 150 mg. (3)
---------------------------------CONTRAINDICATIONS--------------------------------
• None. (4)
--------------------------WARNINGS AND PRECAUTIONS---------------------------
• Interstitial Lung Disease (ILD)-like events, including fatalities have been infrequently reported. Interrupt TARCEVA if acute onset of new or progressive unexplained pulmonary symptoms, such
FULL PRESCRIBING INFORMATION: CONTENTS *
1 INDICATIONS AND USAGE
1.1 Non-Small Cell Lung Cancer (NSCLC) 1.2 Pancreatic Cancer
2 DOSAGE AND ADMINISTRATION
2.1 2.2 2.3
Recommended Dose – NSCLC Recommended Dose – Pancreatic Cancer Dose Modifications
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Pulmonary Toxicity 5.2 Renal Failure 5.3 Hepatotoxicity 5.4 Patients with Hepatic Impairment 5.5 Gastrointestinal perforation
5.6 Bullous and exfoliative skin disorders 5.7 Myocardial infarction/ischemia 5.8 Cerebrovascular accident 5.9 Microangiopathic Hemolytic Anemia with Thrombocytopenia 5.10 Ocular Disorders
5.11 Elevated International Normalized Ratio and Potential Bleeding 5.12 Use in Pregnancy
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience 6.2 Post-Marketing Experience
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1 Non-Small Cell Lung Cancer (NSCLC)
TARCEVA monotherapy is indicated for the maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer whose disease has not progressed after four cycles of platinum- based first-line chemotherapy [see Clinical Studies (14.1)]. TARCEVA monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen [see Clinical Studies (14.2)].
Results from two, multicenter, placebo-controlled, randomized, Phase 3 trials conducted in first-line patients with locally advanced or metastatic NSCLC showed no clinical benefit with the concurrent administration of TARCEVA with platinum-based chemotherapy [carboplatin and paclitaxel or gemcitabine and cisplatin] and its use is not recommended in that setting [see Clinical Studies (14.3)].
1.2 Pancreatic Cancer
TARCEVA in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer [see Clinical Studies (14.4)].
2 DOSAGE AND ADMINISTRATION
2.1 NSCLC
The recommended daily dose of TARCEVA for NSCLC is 150 mg taken on an empty stomach at least one hour before or two hours after the ingestion of food. Treatment should continue until disease progression or unacceptable toxicity occurs. There is no evidence that treatment beyond progression is beneficial.
14.1
14.2 14.3 14.4
Non-Small Cell Lung Cancer (NSCLC) – TARCEVA monotherapy administered as maintenance treatment NSCLC – TARCEVA administered as a Single-agent NSCLC – TARCEVA Administered Concurrently with Chemotherapy
Pancreatic Cancer – TARCEVA Administered Concurrently with Gemcitabine
16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
2.2 Pancreatic Cancer
The recommended daily dose of TARCEVA for pancreatic cancer is 100 mg taken on an empty stomach at least one hour before or two hours after the ingestion of food, in combination with gemcitabine [see Clinical Studies (14.4) or the gemcitabine package insert]. Treatment should continue until disease progression or unacceptable toxicity occurs.
2.3 Dose Modifications
In patients who develop an acute onset of new or progressive pulmonary symptoms, such as dyspnea, cough or fever, treatment with TARCEVA should be interrupted pending diagnostic evaluation. If Interstitial Lung Disease (ILD) is diagnosed, TARCEVA should be discontinued and appropriate treatment instituted as necessary [see Warnings and Precautions (5.1)]. Discontinue TARCEVA for hepatic failure or gastrointestinal perforation. Interrupt or discontinue TARCEVA in patients with dehydration who are at risk for renal failure, in patients with severe bullous, blistering or exfoliative skin conditions, or in patients with acute/worsening ocular disorders [see Warnings and Precautions (5.2, 5.3, 5.4, 5.5, 5.6, 5.10)]. Diarrhea can usually be managed with loperamide. Patients with severe diarrhea who are unresponsive to loperamide or who become dehydrated may require dose reduction or temporary interruption of therapy. Patients with severe skin reactions may also require dose reduction or temporary interruption of therapy. When dose reduction is necessary, the TARCEVA dose should be reduced in 50 mg decrements.
In patients who are taking TARCEVA with a strong CYP3A4 inhibitor such as, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole, or grapefruit or grapefruit juice, a dose reduction should be considered if severe adverse reactions occur. Similarly, in patients who are taking TARCEVA with an inhibitor of both CYP3A4 and CYP1A2 like ciprofloxacin, a dose reduction of TARCEVA should be considered if severe adverse reactions occur [see Drug Interactions (7)].
as dyspnea, cough and fever occur. Discontinue TARCEVA if ILD is diagnosed. (5.1) • Cases of acute renal failure (including fatalities), and renal insufficiency have been reported.
Interrupt TARCEVA in the event of dehydration. Monitor renal function and electrolytes in patients
at risk of dehydration. (5.2) • Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported.
Monitor periodic liver function testing. Interrupt or discontinue TARCEVA if liver function changes
are severe. (5.3) • Monitor patients with hepatic impairment closely. Interrupt or discontinue TARCEVA if changes in
liver function are severe (5.4) • Gastrointestinal perforations, including fatalities, have been reported. Discontinue TARCEVA. (5.5) • Bullous and exfoliative skin disorders, including fatalities, have been reported. Interrupt or
discontinue TARCEVA (5.6) • Myocardial infarction/ischemia has been reported, including fatalities, in patients with pancreatic
cancer. (5.7) • Cerebrovascular accidents, including a fatality, have been reported in patients with pancreatic
cancer. (5.8) • Microangiopathic Hemolytic Anemia with thrombocytopenia has been reported in patients with
pancreatic cancer. (5.9) • Corneal perforation and ulceration have been reported. Interrupt or discontinue TARCEVA (5.10) • International Normalized Ratio (INR) elevations and bleeding events, some associated with
concomitant warfarin administration have been reported. Monitor patients taking warfarin or other
coumarin-derivative anticoagulants. (5.11) • TARCEVA can cause fetal harm when administered to a pregnant woman. Women should be
advised to avoid pregnancy while on TARCEVA. (5.12)
--------------------------------ADVERSE REACTIONS---------------------------------
• The most common adverse reactions (>20%) in maintenance treatment are rash-like events and diarrhea. (6)
• The most common adverse reactions (>20%) in 2nd line NSCLC are rash, diarrhea, anorexia, fatigue, dyspnea, cough, nausea, infection and vomiting. (6)
• The most common adverse reactions (>20%) in pancreatic cancer are fatigue, rash, nausea, anorexia, diarrhea, abdominal pain, vomiting, weight decrease, infection, edema, pyrexia, constipation, bone pain, dyspnea, stomatitis and myalgia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact OSI Pharmaceuticals Inc. at 1-800-572-1932 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
--------------------------------DRUG INTERACTIONS---------------------------------
• CYP3A4 inhibitors may increase erlotinib plasma concentrations. (7) • CYP3A4 inducers may decrease erlotinib plasma concentrations. (7) • CYP1A2 inducers may decrease erlotinib plasma concentrations. (7) • Erlotinib solubility is pH dependent. Drugs that alter the pH of the upper GI tract may alter the
solubility of erlotinib and hence its absorption. (7) • Cigarette smoking decreases erlotinib plasma concentrations (7)
See 17 for PATIENT COUNSELING INFORMATION. Revised: [4/2010]
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Gender 8.7 Race 8.8 Patients with Hepatic Impairment 8.9 Patients with Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action 12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TARCEVA safely and effectively. See full prescribing information for TARCEVA.
TARCEVA® (erlotinib) tablets, oral Initial U.S. Approval: 2004
----------------------------RECENT MAJOR CHANGES---------------------------
Indications and Usage (1.1) Warnings and Precautions, Gastrointestinal Perforation (5.5) Warnings and Precautions, Bullous Skin Disorders (5.6) Warnings and Precautions, Ocular Disorders (5.10)
04/2010 04/2009 04/2009 04/2009
-------------------------------INDICATIONS AND USAGE-----------------------------
TARCEVA is a kinase inhibitor indicated for:
•
•
•
Maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. (1.1) Treatment of locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. (1.1) First-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer, in combination with gemcitabine. (1.2)
--------------------------DOSAGE AND ADMINISTRATION---------------------------
• The dose for NSCLC is 150 mg/day. (2.1) • The dose for pancreatic cancer is 100 mg/day. (2.2) • All doses of TARCEVA should be taken on an empty stomach at least one hour before or two hours
after food. (2.1, 2.2)
• Reduce in 50 mg decrements, when necessary. (2.3)
------------------------DOSAGE FORMS AND STRENGTHS-------------------------
• Tablets: 25 mg, 100 mg and 150 mg. (3)
---------------------------------CONTRAINDICATIONS--------------------------------
• None. (4)
--------------------------WARNINGS AND PRECAUTIONS---------------------------
• Interstitial Lung Disease (ILD)-like events, including fatalities have been infrequently reported. Interrupt TARCEVA if acute onset of new or progressive unexplained pulmonary symptoms, such
FULL PRESCRIBING INFORMATION: CONTENTS *
1 INDICATIONS AND USAGE
1.1 Non-Small Cell Lung Cancer (NSCLC) 1.2 Pancreatic Cancer
2 DOSAGE AND ADMINISTRATION
2.1 2.2 2.3
Recommended Dose – NSCLC Recommended Dose – Pancreatic Cancer Dose Modifications
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Pulmonary Toxicity 5.2 Renal Failure 5.3 Hepatotoxicity 5.4 Patients with Hepatic Impairment 5.5 Gastrointestinal perforation
5.6 Bullous and exfoliative skin disorders 5.7 Myocardial infarction/ischemia 5.8 Cerebrovascular accident 5.9 Microangiopathic Hemolytic Anemia with Thrombocytopenia 5.10 Ocular Disorders
5.11 Elevated International Normalized Ratio and Potential Bleeding 5.12 Use in Pregnancy
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience 6.2 Post-Marketing Experience
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1 Non-Small Cell Lung Cancer (NSCLC)
TARCEVA monotherapy is indicated for the maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer whose disease has not progressed after four cycles of platinum- based first-line chemotherapy [see Clinical Studies (14.1)]. TARCEVA monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen [see Clinical Studies (14.2)].
Results from two, multicenter, placebo-controlled, randomized, Phase 3 trials conducted in first-line patients with locally advanced or metastatic NSCLC showed no clinical benefit with the concurrent administration of TARCEVA with platinum-based chemotherapy [carboplatin and paclitaxel or gemcitabine and cisplatin] and its use is not recommended in that setting [see Clinical Studies (14.3)].
1.2 Pancreatic Cancer
TARCEVA in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer [see Clinical Studies (14.4)].
2 DOSAGE AND ADMINISTRATION
2.1 NSCLC
The recommended daily dose of TARCEVA for NSCLC is 150 mg taken on an empty stomach at least one hour before or two hours after the ingestion of food. Treatment should continue until disease progression or unacceptable toxicity occurs. There is no evidence that treatment beyond progression is beneficial.
14.1
14.2 14.3 14.4
Non-Small Cell Lung Cancer (NSCLC) – TARCEVA monotherapy administered as maintenance treatment NSCLC – TARCEVA administered as a Single-agent NSCLC – TARCEVA Administered Concurrently with Chemotherapy
Pancreatic Cancer – TARCEVA Administered Concurrently with Gemcitabine
16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
2.2 Pancreatic Cancer
The recommended daily dose of TARCEVA for pancreatic cancer is 100 mg taken on an empty stomach at least one hour before or two hours after the ingestion of food, in combination with gemcitabine [see Clinical Studies (14.4) or the gemcitabine package insert]. Treatment should continue until disease progression or unacceptable toxicity occurs.
2.3 Dose Modifications
In patients who develop an acute onset of new or progressive pulmonary symptoms, such as dyspnea, cough or fever, treatment with TARCEVA should be interrupted pending diagnostic evaluation. If Interstitial Lung Disease (ILD) is diagnosed, TARCEVA should be discontinued and appropriate treatment instituted as necessary [see Warnings and Precautions (5.1)]. Discontinue TARCEVA for hepatic failure or gastrointestinal perforation. Interrupt or discontinue TARCEVA in patients with dehydration who are at risk for renal failure, in patients with severe bullous, blistering or exfoliative skin conditions, or in patients with acute/worsening ocular disorders [see Warnings and Precautions (5.2, 5.3, 5.4, 5.5, 5.6, 5.10)]. Diarrhea can usually be managed with loperamide. Patients with severe diarrhea who are unresponsive to loperamide or who become dehydrated may require dose reduction or temporary interruption of therapy. Patients with severe skin reactions may also require dose reduction or temporary interruption of therapy. When dose reduction is necessary, the TARCEVA dose should be reduced in 50 mg decrements.
In patients who are taking TARCEVA with a strong CYP3A4 inhibitor such as, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole, or grapefruit or grapefruit juice, a dose reduction should be considered if severe adverse reactions occur. Similarly, in patients who are taking TARCEVA with an inhibitor of both CYP3A4 and CYP1A2 like ciprofloxacin, a dose reduction of TARCEVA should be considered if severe adverse reactions occur [see Drug Interactions (7)].
Pre-treatment with the CYP3A4 inducer rifampicin decreased erlotinib AUC by about 2/3 to 4/5. Use of alternative treatments lacking CYP3A4 inducing activity is strongly recommended. If an alternative treatment is unavailable, an increase in the dose of TARCEVA should be considered as tolerated at two week intervals while monitoring the patient’s safety. The maximum dose of TARCEVA studied in combination with rifampicin is 450 mg. If the TARCEVA dose is adjusted upward, the dose will need to be reduced immediately to the indicated starting dose upon discontinuation of rifampicin or other inducers. Other CYP3A4 inducers include, but are not limited to rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital and St. John’s Wort. These too should be avoided if possible [see Drug Interactions (7)]. Cigarette smoking has been shown to reduce erlotinib exposure. Patients should be advised to stop smoking. If a patient continues to smoke, a cautious increase in the dose of TARCEVA, not exceeding 300 mg may be considered, while monitoring the patient’s safety. However, efficacy and long-term safety (> 14 days) of a dose higher than the recommended starting doses have not been established in patients who continue to smoke cigarettes. If the TARCEVA dose is adjusted upward, the dose should be reduced immediately to the indicated starting dose upon cessation of smoking [see Clinical Pharmacology (12.3)]. Erlotinib is eliminated by hepatic metabolism and biliary excretion. Although erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh B), patients with hepatic impairment (total bilirubin > ULN or Child-Pugh A, B and C) should be closely monitored during therapy with TARCEVA [see Warnings and Precautions (5.4)]. Treatment with TARCEVA should be used with extra caution in patients with total bilirubin > 3 x ULN. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe such as doubling of total bilirubin and/or tripling of transaminases in the setting of pretreatment values outside normal range. In the setting of worsening liver function
tests, before they become severe, dose interruption and/or dose reduction with frequent liver function test monitoring should be considered. TARCEVA dosing should be interrupted or discontinued if total bilirubin is >3 x ULN and/or transaminases are >5 x ULN in the setting of normal pretreatment values [see Warnings and Precautions (5.3, 5.4), Adverse Reactions (6.1, 6.2) and Use in Specific Populations (8.8].
3 DOSAGE FORMS AND STRENGTHS
25 mg tablets White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in orange with a “T” and “25” on one side and plain on the other side. 100 mg tablets White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in gray with “T” and “100” on one side and plain on the other side. 150 mg tablets White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in maroon with “T” and “150” on one side and plain on the other side.
5.8 Cerebrovascular Accident
In the pancreatic carcinoma trial, six patients in the TARCEVA/gemcitabine group developed cerebrovascular accidents (incidence: 2.3%). One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo/gemcitabine group there were no cerebrovascular accidents.
5.9 Microangiopathic Hemolytic Anemia with Thrombocytopenia
In the pancreatic carcinoma trial, two patients in the TARCEVA/gemcitabine group developed microangiopathic hemolytic anemia with thrombocytopenia (incidence: 0.8%). Both patients received TARCEVA and gemcitabine concurrently. In comparison, in the placebo/gemcitabine group there were no cases of microangiopathic hemolytic anemia with thrombocytopenia.
5.10 Ocular Disorders
Corneal perforation or ulceration have been reported during use of TARCEVA. Other ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis have been observed with TARCEVA treatment and are known risk factors for corneal ulceration/perforation [see Adverse Reactions (6.1)]. Interrupt or discontinue TARCEVA therapy if patients present with acute/worsening ocular disorders such as eye pain.
5.11 Elevated International Normalized Ratio and Potential Bleeding
International Normalized Ratio (INR) elevations and infrequent reports of bleeding events, including gastrointestinal and non-gastrointestinal bleeding, have been reported in clinical studies, some associated with concomitant warfarin administration. Patients taking warfarin or other coumarin- derivative anticoagulants should be monitored regularly for changes in prothrombin time or INR [see Adverse Reactions (6.1)].
5.12 Use in Pregnancy
TARCEVA can cause fetal harm when administered to a pregnant woman. Erlotinib administered to rabbits during organogenesis at doses that result in plasma drug concentrations of approximately 3 times those in humans at the recommended dose of 150 mg daily, was associated with embryofetal lethality and abortion. When erlotinib was administered to female rats prior to mating and through the first week of pregnancy, at doses 0.3 or 0.7 times the clinical dose of 150 mg, on a mg/m2 basis, there was an increase in early resorptions that resulted in a decrease in the number of live fetuses [see Use in Specific Populations (8.1)]. There are no adequate and well-controlled studies in pregnant women using TARCEVA. Women of childbearing potential should be advised to avoid pregnancy while on TARCEVA. Adequate contraceptive methods should be used during therapy, and for at least 2 weeks after completing therapy. If TARCEVA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
6 ADVERSE REACTIONS
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Safety evaluation of TARCEVA is based on more than 1200 cancer patients who received TARCEVA as monotherapy, more than 300 patients who received TARCEVA 100 or 150 mg plus gemcitabine, and 1228 patients who received TARCEVA concurrently with other chemotherapies. There have been reports of serious events, including fatalities, in patients receiving TARCEVA for treatment of NSCLC, pancreatic cancer or other advanced solid tumors [see Warnings and Precautions (5) and Dosage and Administration (2.3)].
6.1 Clinical Trial Experience
Non-Small Cell Lung Cancer
Maintenance Study
Adverse reactions, regardless of causality, that occurred in at least 3% of patients treated with single- agent TARCEVA at 150 mg and at least 3% more often than in the placebo group in the randomized maintenance trial are summarized by NCI-CTC (version 3.0) Grade in Table 1. The most common adverse reactions in patients receiving single-agent TARCEVA 150 mg were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 6.0% and 1.8%, respectively, in TARCEVA-treated patients. Rash and diarrhea resulted in study discontinuation in 1.2% and 0.5% of TARCEVA-treated patients, respectively. Dose reduction or interruption for rash and diarrhea was needed in 5.1% and 2.8% of patients, respectively. In TARCEVA-treated patients who developed rash, the onset was within two weeks in 66% and within one month in 81%.
Table 1: NSCLC Maintenance Study: Adverse Reactions Occurring More Frequently (≥ 3%) in the Single-Agent TARCEVA Group than in the Placebo Group and in ≥ 3% of Patients in the TARCEVA Group.
Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) were observed in patients receiving single-agent TARCEVA 150 mg in the Maintenance study. Grade 2 (>2.5 – 5.0 x ULN) ALT elevations occurred in 2% and 1%, and Grade 3 (>5.0 – 20.0 x ULN) ALT elevations were observed in 1% and 0% of TARCEVA and placebo treated patients, respectively. The TARCEVA treatment group had Grade 2 (>1.5-3.0 x ULN) bilirubin elevations in 4% and Grade 3 (>3.0-10.0 x ULN) in <1% compared with <1% for both Grades 2 and 3 in the placebo group. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe [see Dosage and Administration (2.3)].
Second/Third Line Study
Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with single- agent TARCEVA at 150 mg and at least 3% more often than in the placebo group in the randomized trial of patients with NSCLC are summarized by NCI-CTC (version 2.0) Grade in Table 2. The most common adverse reactions in this patient population were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 9% and 6%, respectively, in TARCEVA-treated patients. Rash and diarrhea each resulted in study discontinuation in 1% of TARCEVA-treated patients. Six percent and 1% of patients needed dose reduction for rash and diarrhea, respectively. The median time to onset of rash was 8 days, and the median time to onset of diarrhea was 12 days.
4
None
5
5.1
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
Pulmonary Toxicity
There have been reports of serious Interstitial Lung Disease (ILD)-like events, including fatalities, in patients receiving TARCEVA for treatment of NSCLC, pancreatic cancer or other advanced solid tumors. In the randomized single-agent NSCLC-studies [see Clinical Studies (14.1, 14.2)], the incidence of serious ILD-like events in the TARCEVA treated patients versus placebo treated patients was 0.7% versus 0% in the maintenance study and 0.8% for both groups in the 2nd and 3rd line study. In the pancreatic cancer study – in combination with gemcitabine – [see Clinical Studies (14.4)], the incidence of ILD-like events was 2.5% in the TARCEVA plus gemcitabine group vs. 0.4% in the placebo plus gemcitabine group. The overall incidence of ILD-like events in approximately 32,000 TARCEVA-treated patients from all studies (including uncontrolled studies and studies with concurrent chemotherapy) was approximately 1.1%. Reported diagnoses in patients suspected of having ILD-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, Acute Respiratory Distress Syndrome and lung infiltration. Symptoms started from 5 days to more than 9 months (median 39 days) after initiating TARCEVA therapy. In the lung cancer trials most of the cases were associated with confounding or contributing factors such as concomitant/prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary infections. In the event of an acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever, TARCEVA therapy should be interrupted pending diagnostic evaluation. If ILD is diagnosed, TARCEVA should be discontinued and appropriate treatment instituted as needed [see Dosage and Administration (2.3)].
5.2 Renal Failure
Cases of hepatorenal syndrome, acute renal failure (including fatalities), and renal insufficiency have been reported. Some were secondary to baseline hepatic impairment while others were associated with severe dehydration due to diarrhea, vomiting, and/or anorexia or concurrent chemotherapy use. In the event of dehydration, particularly in patients with contributing risk factors for renal failure (eg, pre-existing renal disease, medical conditions or medications that may lead to renal disease, or other predisposing conditions including advanced age), TARCEVA therapy should be interrupted and appropriate measures should be taken to intensively rehydrate the patient. Periodic monitoring of renal function and serum electrolytes is recommended in patients at risk of dehydration [see Adverse Reactions (6.1) and Dosage and Administration (2.3)].
5.3 Hepatotoxicity
Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported during use of TARCEVA, particularly in patients with baseline hepatic impairment. Therefore, periodic liver function testing (transaminases, bilirubin, and alkaline phosphatase) is recommended. In the setting of worsening liver function tests, dose interruption and/or dose reduction with frequent liver function test monitoring should be considered. TARCEVA dosing should be interrupted or discontinued if total bilirubin is >3 x ULN and/or transaminases are >5 x ULN in the setting of normal pretreatment values [see Adverse Reactions (6.1, 6.2) and Dosage and Administration (2.3)].
5.4 Patients with Hepatic Impairment
In a pharmacokinetic study in patients with moderate hepatic impairment (Child-Pugh B) associated with significant liver tumor burden, 10 out of 15 patients died on treatment or within 30 days of the last TARCEVA dose. One patient died from hepatorenal syndrome, 1 patient died from rapidly progressing liver failure and the remaining 8 patients died from progressive disease. Six out of the 10 patients who died had baseline total bilirubin > 3 x ULN suggesting severe hepatic impairment. Treatment with TARCEVA should be used with extra caution in patients with total bilirubin > 3 x ULN. Patients with hepatic impairment (total bilirubin > ULN or Child-Pugh A, B and C) should be closely monitored during therapy with TARCEVA. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe such as doubling of total bilirubin and/or tripling of transaminases in the setting of pretreatment values outside normal range [see Clinical Pharmacology (12.3) and Dosage and Administration (2.3)].
5.5 Gastrointestinal Perforation
Gastrointestinal perforation (including fatalities) have been reported in patients receiving TARCEVA. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease are at increased risk. [see Adverse Reactions (6.1, 6.2)]. Permanently discontinue TARCEVA in patients who develop gastrointestinal perforation.
5.6 Bullous and Exfoliative Skin Disorders
Bullous, blistering and exfoliative skin conditions have been reported including cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some cases were fatal [see Adverse Reactions (6.1, 6.2)]. Interrupt or discontinue TARCEVA treatment if the patient develops severe bullous, blistering or exfoliating conditions.
5.7 Myocardial Infarction/Ischemia
In the pancreatic carcinoma trial, six patients (incidence of 2.3%) in the TARCEVA/gemcitabine group developed myocardial infarction/ischemia. One of these patients died due to myocardial infarction. In comparison, 3 patients in the placebo/gemcitabine group developed myocardial infarction (incidence 1.2%) and one died due to myocardial infarction.
tests, before they become severe, dose interruption and/or dose reduction with frequent liver function test monitoring should be considered. TARCEVA dosing should be interrupted or discontinued if total bilirubin is >3 x ULN and/or transaminases are >5 x ULN in the setting of normal pretreatment values [see Warnings and Precautions (5.3, 5.4), Adverse Reactions (6.1, 6.2) and Use in Specific Populations (8.8].
3 DOSAGE FORMS AND STRENGTHS
25 mg tablets White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in orange with a “T” and “25” on one side and plain on the other side. 100 mg tablets White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in gray with “T” and “100” on one side and plain on the other side. 150 mg tablets White film-coated tablets for daily oral administration. Round, biconvex face and straight sides, white film-coated, printed in maroon with “T” and “150” on one side and plain on the other side.
5.8 Cerebrovascular Accident
In the pancreatic carcinoma trial, six patients in the TARCEVA/gemcitabine group developed cerebrovascular accidents (incidence: 2.3%). One of these was hemorrhagic and was the only fatal event. In comparison, in the placebo/gemcitabine group there were no cerebrovascular accidents.
5.9 Microangiopathic Hemolytic Anemia with Thrombocytopenia
In the pancreatic carcinoma trial, two patients in the TARCEVA/gemcitabine group developed microangiopathic hemolytic anemia with thrombocytopenia (incidence: 0.8%). Both patients received TARCEVA and gemcitabine concurrently. In comparison, in the placebo/gemcitabine group there were no cases of microangiopathic hemolytic anemia with thrombocytopenia.
5.10 Ocular Disorders
Corneal perforation or ulceration have been reported during use of TARCEVA. Other ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis have been observed with TARCEVA treatment and are known risk factors for corneal ulceration/perforation [see Adverse Reactions (6.1)]. Interrupt or discontinue TARCEVA therapy if patients present with acute/worsening ocular disorders such as eye pain.
5.11 Elevated International Normalized Ratio and Potential Bleeding
International Normalized Ratio (INR) elevations and infrequent reports of bleeding events, including gastrointestinal and non-gastrointestinal bleeding, have been reported in clinical studies, some associated with concomitant warfarin administration. Patients taking warfarin or other coumarin- derivative anticoagulants should be monitored regularly for changes in prothrombin time or INR [see Adverse Reactions (6.1)].
5.12 Use in Pregnancy
TARCEVA can cause fetal harm when administered to a pregnant woman. Erlotinib administered to rabbits during organogenesis at doses that result in plasma drug concentrations of approximately 3 times those in humans at the recommended dose of 150 mg daily, was associated with embryofetal lethality and abortion. When erlotinib was administered to female rats prior to mating and through the first week of pregnancy, at doses 0.3 or 0.7 times the clinical dose of 150 mg, on a mg/m2 basis, there was an increase in early resorptions that resulted in a decrease in the number of live fetuses [see Use in Specific Populations (8.1)]. There are no adequate and well-controlled studies in pregnant women using TARCEVA. Women of childbearing potential should be advised to avoid pregnancy while on TARCEVA. Adequate contraceptive methods should be used during therapy, and for at least 2 weeks after completing therapy. If TARCEVA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
6 ADVERSE REACTIONS
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Safety evaluation of TARCEVA is based on more than 1200 cancer patients who received TARCEVA as monotherapy, more than 300 patients who received TARCEVA 100 or 150 mg plus gemcitabine, and 1228 patients who received TARCEVA concurrently with other chemotherapies. There have been reports of serious events, including fatalities, in patients receiving TARCEVA for treatment of NSCLC, pancreatic cancer or other advanced solid tumors [see Warnings and Precautions (5) and Dosage and Administration (2.3)].
6.1 Clinical Trial Experience
Non-Small Cell Lung Cancer
Maintenance Study
Adverse reactions, regardless of causality, that occurred in at least 3% of patients treated with single- agent TARCEVA at 150 mg and at least 3% more often than in the placebo group in the randomized maintenance trial are summarized by NCI-CTC (version 3.0) Grade in Table 1. The most common adverse reactions in patients receiving single-agent TARCEVA 150 mg were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 6.0% and 1.8%, respectively, in TARCEVA-treated patients. Rash and diarrhea resulted in study discontinuation in 1.2% and 0.5% of TARCEVA-treated patients, respectively. Dose reduction or interruption for rash and diarrhea was needed in 5.1% and 2.8% of patients, respectively. In TARCEVA-treated patients who developed rash, the onset was within two weeks in 66% and within one month in 81%.
Table 1: NSCLC Maintenance Study: Adverse Reactions Occurring More Frequently (≥ 3%) in the Single-Agent TARCEVA Group than in the Placebo Group and in ≥ 3% of Patients in the TARCEVA Group.
Liver function test abnormalities (including elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) were observed in patients receiving single-agent TARCEVA 150 mg in the Maintenance study. Grade 2 (>2.5 – 5.0 x ULN) ALT elevations occurred in 2% and 1%, and Grade 3 (>5.0 – 20.0 x ULN) ALT elevations were observed in 1% and 0% of TARCEVA and placebo treated patients, respectively. The TARCEVA treatment group had Grade 2 (>1.5-3.0 x ULN) bilirubin elevations in 4% and Grade 3 (>3.0-10.0 x ULN) in <1% compared with <1% for both Grades 2 and 3 in the placebo group. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe [see Dosage and Administration (2.3)].
Second/Third Line Study
Adverse reactions, regardless of causality, that occurred in at least 10% of patients treated with single- agent TARCEVA at 150 mg and at least 3% more often than in the placebo group in the randomized trial of patients with NSCLC are summarized by NCI-CTC (version 2.0) Grade in Table 2. The most common adverse reactions in this patient population were rash and diarrhea. Grade 3/4 rash and diarrhea occurred in 9% and 6%, respectively, in TARCEVA-treated patients. Rash and diarrhea each resulted in study discontinuation in 1% of TARCEVA-treated patients. Six percent and 1% of patients needed dose reduction for rash and diarrhea, respectively. The median time to onset of rash was 8 days, and the median time to onset of diarrhea was 12 days.
4
None
5
5.1
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
Pulmonary Toxicity
There have been reports of serious Interstitial Lung Disease (ILD)-like events, including fatalities, in patients receiving TARCEVA for treatment of NSCLC, pancreatic cancer or other advanced solid tumors. In the randomized single-agent NSCLC-studies [see Clinical Studies (14.1, 14.2)], the incidence of serious ILD-like events in the TARCEVA treated patients versus placebo treated patients was 0.7% versus 0% in the maintenance study and 0.8% for both groups in the 2nd and 3rd line study. In the pancreatic cancer study – in combination with gemcitabine – [see Clinical Studies (14.4)], the incidence of ILD-like events was 2.5% in the TARCEVA plus gemcitabine group vs. 0.4% in the placebo plus gemcitabine group. The overall incidence of ILD-like events in approximately 32,000 TARCEVA-treated patients from all studies (including uncontrolled studies and studies with concurrent chemotherapy) was approximately 1.1%. Reported diagnoses in patients suspected of having ILD-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, Acute Respiratory Distress Syndrome and lung infiltration. Symptoms started from 5 days to more than 9 months (median 39 days) after initiating TARCEVA therapy. In the lung cancer trials most of the cases were associated with confounding or contributing factors such as concomitant/prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary infections. In the event of an acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever, TARCEVA therapy should be interrupted pending diagnostic evaluation. If ILD is diagnosed, TARCEVA should be discontinued and appropriate treatment instituted as needed [see Dosage and Administration (2.3)].
5.2 Renal Failure
Cases of hepatorenal syndrome, acute renal failure (including fatalities), and renal insufficiency have been reported. Some were secondary to baseline hepatic impairment while others were associated with severe dehydration due to diarrhea, vomiting, and/or anorexia or concurrent chemotherapy use. In the event of dehydration, particularly in patients with contributing risk factors for renal failure (eg, pre-existing renal disease, medical conditions or medications that may lead to renal disease, or other predisposing conditions including advanced age), TARCEVA therapy should be interrupted and appropriate measures should be taken to intensively rehydrate the patient. Periodic monitoring of renal function and serum electrolytes is recommended in patients at risk of dehydration [see Adverse Reactions (6.1) and Dosage and Administration (2.3)].
5.3 Hepatotoxicity
Cases of hepatic failure and hepatorenal syndrome (including fatalities) have been reported during use of TARCEVA, particularly in patients with baseline hepatic impairment. Therefore, periodic liver function testing (transaminases, bilirubin, and alkaline phosphatase) is recommended. In the setting of worsening liver function tests, dose interruption and/or dose reduction with frequent liver function test monitoring should be considered. TARCEVA dosing should be interrupted or discontinued if total bilirubin is >3 x ULN and/or transaminases are >5 x ULN in the setting of normal pretreatment values [see Adverse Reactions (6.1, 6.2) and Dosage and Administration (2.3)].
5.4 Patients with Hepatic Impairment
In a pharmacokinetic study in patients with moderate hepatic impairment (Child-Pugh B) associated with significant liver tumor burden, 10 out of 15 patients died on treatment or within 30 days of the last TARCEVA dose. One patient died from hepatorenal syndrome, 1 patient died from rapidly progressing liver failure and the remaining 8 patients died from progressive disease. Six out of the 10 patients who died had baseline total bilirubin > 3 x ULN suggesting severe hepatic impairment. Treatment with TARCEVA should be used with extra caution in patients with total bilirubin > 3 x ULN. Patients with hepatic impairment (total bilirubin > ULN or Child-Pugh A, B and C) should be closely monitored during therapy with TARCEVA. TARCEVA dosing should be interrupted or discontinued if changes in liver function are severe such as doubling of total bilirubin and/or tripling of transaminases in the setting of pretreatment values outside normal range [see Clinical Pharmacology (12.3) and Dosage and Administration (2.3)].
5.5 Gastrointestinal Perforation
Gastrointestinal perforation (including fatalities) have been reported in patients receiving TARCEVA. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease are at increased risk. [see Adverse Reactions (6.1, 6.2)]. Permanently discontinue TARCEVA in patients who develop gastrointestinal perforation.
5.6 Bullous and Exfoliative Skin Disorders
Bullous, blistering and exfoliative skin conditions have been reported including cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some cases were fatal [see Adverse Reactions (6.1, 6.2)]. Interrupt or discontinue TARCEVA treatment if the patient develops severe bullous, blistering or exfoliating conditions.
5.7 Myocardial Infarction/Ischemia
In the pancreatic carcinoma trial, six patients (incidence of 2.3%) in the TARCEVA/gemcitabine group developed myocardial infarction/ischemia. One of these patients died due to myocardial infarction. In comparison, 3 patients in the placebo/gemcitabine group developed myocardial infarction (incidence 1.2%) and one died due to myocardial infarction.
7 DRUG INTERACTIONS
Erlotinib is metabolized predominantly by CYP3A4, and inhibitors of CYP3A4 would be expected to increase exposure. Co-treatment with the potent CYP3A4 inhibitor ketoconazole increased erlotinib AUC by 2/3. When TARCEVA was co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2, the erlotinib exposure [AUC] and maximum concentration [Cmax] increased by 39% and 17% respectively. Caution should be used when administering or taking TARCEVA with ketoconazole and other strong CYP3A4 inhibitors such as, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole and grapefruit or grapefruit juice [see Dosage and Administration (2.3)].
Pre-treatment with the CYP3A4 inducer rifampicin for 7 days prior to TARCEVA decreased erlotinib AUC by about 2/3 to 4/5, which is equivalent to a dose of about 30 to 50 mg in NSCLC patients. In a separate study, treatment with rifampicin for 11 days, with co-administration of a single 450 mg dose of TARCEVA on day 8 resulted in a mean erlotinib exposure (AUC) that was 57.6% of that observed following a single 150 mg TARCEVA dose in the absence of rifampicin treatment [see Dose Modifications (2.3)]. Use of alternative treatments lacking CYP3A4 inducing activity is strongly recommended. If an alternative treatment is unavailable, adjusting the starting dose should be considered. If the TARCEVA dose is adjusted upward, the dose will need to be reduced immediately to the indicated starting dose upon discontinuation of rifampicin or other inducers. Other CYP3A4 inducers include, but are not limited to, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital and St. John’s Wort [see Dosage and Administration (2.3)].
Cigarette smoking has been shown to reduce erlotinib AUC. Patients should be advised to stop smoking; however, if they continue to smoke, a cautious increase in the dose of TARCEVA may be considered, while monitoring the patient’s safety. If the TARCEVA dose is adjusted upward, the dose should be reduced immediately to the indicated starting dose upon cessation of smoking [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
Pretreatment and co-administration of TARCEVA decreased the AUC of CYP3A4 substrate, midazolam, by 24%. The mechanism is not clear. In a study, there were no significant effects of gemcitabine on the pharmacokinetics of erlotinib nor were there significant effects of erlotinib on the pharmacokinetics of gemcitabine.
Drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and reduce its bioavailability. Increasing the dose of TARCEVA when co-administered with such agents is not likely to compensate for the loss of exposure. Co-administration of TARCEVA with omeprazole, a proton pump inhibitor, decreased the erlotinib AUC by 46%. Since proton pump inhibitors affect pH of the upper GI tract for an extended period, separation of doses may not eliminate the interaction. The concomitant use of proton pump inhibitors with TARCEVA should be avoided if possible. Co-administration of TARCEVA with 300 mg ranitidine, an H2 receptor antagonist, decreased erlotinib AUC by 33%. When TARCEVA was administered with ranitidine 150 mg twice daily (at least 10 h after the previous ranitidine evening dose and 2 h before the ranitidine morning dose), the erlotinib AUC decreased by 15%. If patients need to be treated with an H2-receptor antagonist such as ranitidine, it should be used in a staggered manner. TARCEVA must be taken once a day, 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of H2-receptor antagonist. Although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the TARCEVA dose should be separated by several hours, if an antacid is necessary. [see Clinical Pharmacology (12.3)].
Erlotinib is metabolized predominantly by CYP3A4, and inhibitors of CYP3A4 would be expected to increase exposure. Co-treatment with the potent CYP3A4 inhibitor ketoconazole increased erlotinib AUC by 2/3. When TARCEVA was co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2, the erlotinib exposure [AUC] and maximum concentration [Cmax] increased by 39% and 17% respectively. Caution should be used when administering or taking TARCEVA with ketoconazole and other strong CYP3A4 inhibitors such as, but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole and grapefruit or grapefruit juice [see Dosage and Administration (2.3)].
Pre-treatment with the CYP3A4 inducer rifampicin for 7 days prior to TARCEVA decreased erlotinib AUC by about 2/3 to 4/5, which is equivalent to a dose of about 30 to 50 mg in NSCLC patients. In a separate study, treatment with rifampicin for 11 days, with co-administration of a single 450 mg dose of TARCEVA on day 8 resulted in a mean erlotinib exposure (AUC) that was 57.6% of that observed following a single 150 mg TARCEVA dose in the absence of rifampicin treatment [see Dose Modifications (2.3)]. Use of alternative treatments lacking CYP3A4 inducing activity is strongly recommended. If an alternative treatment is unavailable, adjusting the starting dose should be considered. If the TARCEVA dose is adjusted upward, the dose will need to be reduced immediately to the indicated starting dose upon discontinuation of rifampicin or other inducers. Other CYP3A4 inducers include, but are not limited to, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital and St. John’s Wort [see Dosage and Administration (2.3)].
Cigarette smoking has been shown to reduce erlotinib AUC. Patients should be advised to stop smoking; however, if they continue to smoke, a cautious increase in the dose of TARCEVA may be considered, while monitoring the patient’s safety. If the TARCEVA dose is adjusted upward, the dose should be reduced immediately to the indicated starting dose upon cessation of smoking [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
Pretreatment and co-administration of TARCEVA decreased the AUC of CYP3A4 substrate, midazolam, by 24%. The mechanism is not clear. In a study, there were no significant effects of gemcitabine on the pharmacokinetics of erlotinib nor were there significant effects of erlotinib on the pharmacokinetics of gemcitabine.
Drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and reduce its bioavailability. Increasing the dose of TARCEVA when co-administered with such agents is not likely to compensate for the loss of exposure. Co-administration of TARCEVA with omeprazole, a proton pump inhibitor, decreased the erlotinib AUC by 46%. Since proton pump inhibitors affect pH of the upper GI tract for an extended period, separation of doses may not eliminate the interaction. The concomitant use of proton pump inhibitors with TARCEVA should be avoided if possible. Co-administration of TARCEVA with 300 mg ranitidine, an H2 receptor antagonist, decreased erlotinib AUC by 33%. When TARCEVA was administered with ranitidine 150 mg twice daily (at least 10 h after the previous ranitidine evening dose and 2 h before the ranitidine morning dose), the erlotinib AUC decreased by 15%. If patients need to be treated with an H2-receptor antagonist such as ranitidine, it should be used in a staggered manner. TARCEVA must be taken once a day, 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of H2-receptor antagonist. Although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the TARCEVA dose should be separated by several hours, if an antacid is necessary. [see Clinical Pharmacology (12.3)].
To read more please visit http://www.tarceva.com/pro_pancreatic/index.jsp. Your going to see that when you do research for this drug that it is for lung,breast,pancreatic and a few other cancers. It is in trail stages for the Brain and hopefully will find a way to help others that are in my dads position. If more studies are done maybe there will be away for future generations to find some sort of cure for this common and devastating cancer. I know everyone is big on breast cancer and prostate but Brain cancer needs to be looked at more closely to. With out our brains we don't exist.
Sites for research:
http://www.cancer.org/cancer/braincnstumorsinadults/index?gclid=CNXf2uWeiq8CFUmc7QodL2DcAA
http://www.milesforhope.org/
http://www.braintumorfoundation.org/
I will be posting as time goes on about this topic. I will also try and answer any questions you all may have or help you into the right direction.
xoxo
